RESEARCH ARTICLE
Lipoic Acid Use and Functional Outcomes
a11111
OPEN ACCESS
Citation: Choi K-H, Park M-S, Kim J-T, Kim H-S,
Kim J-H, Nam T-S, et al. (2016) Lipoic Acid Use
and Functional Outcomes after Thrombolysis in
Patients with Acute Ischemic Stroke and Diabetes.
PLoS ONE 11(9): e0163484. doi:10.1371/journal.
pone.0163484
Editor: Xiaoying Wang, Massachusetts General
Hospital, UNITED STATES
Received: June 23, 2016
Accepted: September 10, 2016
Published: September 27, 2016
Copyright: © 2016 Choi et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper.
Funding: This work was supported by the National
Research Foundation of Korea Grant funded by the
Korean Government (NRF-2013R1A1A1064315,
Choi KH). The funders had no role in study design,
data collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
PLOS ONE | DOI:10.1371/journal.pone.0163484 September 27, 2016
after Thrombolysis in Patients with Acute
Ischemic Stroke and Diabetes
Kang-Ho Choi1,2, Man-Seok Park2*, Joon-Tae Kim2, Hyung-Seok Kim3, Ja-Hae Kim4, Tai-
Seung Nam1, Seong-Min Choi2, Seung-Han Lee2, Byeong-Chae Kim2, Myeong-Kyu Kim2,
Ki-Hyun Cho2
1 Department of Neurology, Chonnam National University Hwasun Hospital, Hwasun, Korea, 2 Department
of Neurology, Chonnam National University Medical School, Gwangju, Korea, 3 Department of Forensic
Medicine, Chonnam National University Medical School, Gwangju, Korea, 4 Department of Nuclear
Medicine, Chonnam National University Medical School, Gwangju, Korea
* mspark@jnu.ac.kr
Abstract
Background
Alpha-lipoic acid (aLA) is a strong antioxidant commonly used for treating diabetic poly-
neuropathy. Previously, we demonstrated the neurorestorative effects of aLA after cerebral
ischemia in rats. However, its effects on patients with stroke remain unknown. We investi-
gated whether patients treated with aLA have better functional outcomes after acute ische-
mic stroke (AIS) and reperfusion therapy than patients not receiving aLA.
Methods
In this retrospective study of 172 prospectively registered patients with diabetes and AIS
treated with tissue plasminogen activator (tPA), we investigated the relationship between
aLA use and functional outcome both after 3 months and after 1 year. The functional out-
comes included occurrence of hemorrhagic transformation (HT), early neurological deterio-
ration (END), and early clinical improvement (ECI). Favorable outcomes were defined as
modified Rankin Scale (mRS) scores of 0–2.
Results
Of the 172 patients with AIS and diabetes, 47 (27.3%) used aLA. In the entire cohort, favor-
able outcomes occurred at significantly higher rates both at 3 months and at 1 year in those
treated with aLA. The risks for END and HT were lower and the occurrence of ECI was
higher in patients treated with aLA. In multivariable analysis, aLA use was associated with
favorable outcomes both at 3 months and at 1 year. Age, HT, and increased National Insti-
tutes of Health Stroke Scale scores were negative predictors of a favorable outcome.
1 / 12
 Lipoic Acid Use and Functional Outcome of Stroke

Conclusions
The use of aLA in patients with AIS and diabetes who are treated with tPA is associated
with favorable outcomes. These results indicate that aLA could be a useful intervention for
the treatment of AIS after reperfusion therapy.

Introduction
Despite significant advances in the prevention and treatment of stroke, it is still one of the lead-
ing causes of death and debilitating disease. Unfortunately, several neuroprotective strategies
have failed in clinical trials. At present, it is reported that there are no pharmacological agents
with putative neuroprotective actions that have demonstrated efficacy in improving outcomes
after ischemic stroke in humans [1]. Therefore, there is a clear need for research to discover
potential neuroprotective agents and new therapeutic strategies.
Previous stroke studies have confirmed that oxidative stress plays an important role in
stroke and in reperfusion following stroke [2]. The ischemic brain is highly susceptible to oxi-
dative damage due to its relatively low levels of protective antioxidants, its high levels of iron,
which acts as a pro-oxidant under pathological conditions, its high concentrations of unsatu-
rated lipids, and its high consumption of oxygen [3]. Paradoxically, the increased delivery of
oxygen to ischemic brain tissue after reperfusion therapy may promote oxidative stress and cell
death due to an increase in free radical generation [4]. Therefore, the use of antioxidants should
be a promising strategy for treating ischemia-reperfusion injury.
Alpha-lipoic acid (aLA) is a strong antioxidant commonly used for the treatment of diabetic
polyneuropathy (DPNP). We previously demonstrated the neuroprotective and neurorestora-
tive effects of aLA, mediated at least partially via insulin receptor activation, after cerebral
ischemia in rats [5]. Moreover, it has been reported that aLA is safe and significantly reduces
oxidative stress levels in aged patients with diabetes mellitus complicated with acute ischemic
stroke (AIS) [6].
To date, however, the effects of aLA on stroke outcome in patients with stroke and diabetes
remain unknown. We investigated whether patients with diabetes treated with aLA have better
functional outcomes after AIS and reperfusion therapy than patients not treated with aLA.

Materials and Methods

Subjects
This was a retrospective study of prospectively registered patients with AIS carried out using a
single-center database. We used data from January 2006 until April 2014. Patients were consec-
utively enrolled if they 1) had AIS and were seen within 4.5 hours of symptom onset, 2) were
treated with intravenous tissue plasminogen activator (IV-tPA), 3) had acute ischemic lesions
on diffusion-weighted imaging (DWI), and 4) had diabetes mellitus with sensory symptoms.
We excluded patients who 1) had previous symptomatic cerebral infarction, 2) had a previous
modified Rankin Scale (mRS) score of 1 or more, 3) had an uncontrolled underlying medical
disease, such as a malignant tumor, severe liver disease (Child-Pugh class B or more), or renal
disease (creatine 3.0mg/dL or more), or 4) were treated with intra-arterial thrombolysis, as
management patterns and devices have changed over the last 10 years.
Baseline clinical information was collected from all patients. Cerebrovascular risk factors
noted are as follows: hypertension (previous use of antihypertensive medication, systolic blood

PLOS ONE | DOI:10.1371/journal.pone.0163484 September 27, 2016 2 / 12

 Lipoic Acid Use and Functional Outcome of Stroke

pressure >140 mmHg, or diastolic blood pressure >90 mmHg at discharge), dyslipidemia
(previous history of lipid-lowering medication), habitual smoking (current or past), and alco-
hol (>2 drinks or 20 g ethanol per day) [7].

Ethics statement
This study was approved by the Institutional Review Board at the Chonnam National Univer-
sity Hospital. All of the clinical investigations described in this study were conducted in accor-
dance with the principles expressed in the Declaration of Helsinki. Written informed consent
was obtained from each patient or a family member.

Clinical assessment and outcome measurements

Demographic characteristics, detailed histories, and clinical information regarding stroke risk
factors were obtained. Physical examinations, routine laboratory tests, chest radiography,
electrocardiography, and brain computed tomography were performed in all patients. The
severity of the neurological deficits was assessed using the National Institutes of Health Stroke
Scale (NIHSS) score, which is composed of 11 items [8]. In all items, a higher score indicates
more severe impairment. The scale ranges from 0–42.
Functional outcomes 3 months and 1 year after the onset of symptoms were measured
using mRS scores. The scores were categorized as favorable (mRS scores of 0–2) or unfavorable
(mRS scores of 3–6) [9]. The mRS consists of 7 levels, ranging from perfect health without
symptoms (mRS score 0) to death (mRS score 6). We defined early neurological deterioration
(END) as an increase of 1 or more points in motor power or an increase of 2 or more points in
total NIHSS score. Early clinical improvement (ECI) was defined as a decrease of 4 or more
points in the NIHSS score within 7 days [10, 11]. Hemorrhagic transformation (HT) was con-
sidered present when one or more of the follow-up gradient echo magnetic resonance imaging
(MRI) or CT scans showed a region consistent with an acute infiltration of blood. Patients
underwent MRI on admission and at day 5. They also underwent CT or an MRI when there
was a worsening of symptoms. Based on clinical and neuro-imaging findings, the patients were
classified based on stroke subtypes according to the Trial of Org. 10172 in Acute Stroke Treat-
ment (TOAST) classification. There were 5 subtypes: 1) large-artery atherosclerosis (LAA), 2)
cardioembolism (CE), 3) small vessel occlusion (SVO), 4) stroke of undetermined etiology
(UD), and 5) stroke of other determined etiology (OE) [12].
We provided the appropriate treatment depending on best practice guidelines established
by the American Heart Association and the American Stroke Association for all patients in this
study [1, 13]. The protocol for therapy of diabetes encouraged, but did not mandate, the use of
drug classes with evidence for reduction of diabetic complications, such as DPNP. These drugs
include aLA, pregabalin, gabapentin, venlafaxine, duloxetine, and tricyclic antidepressants for
patients with diabetes [14]. The use of the specific drug class was based on physicians’ attitudes
regarding the protocol. In addition, aLA was considered for patients who were willing to take
the medicine before meals, as the medication should be taken before meals. In the aLA group,
aLA was administered after overnight fasting within 24 hours of symptom onset based on the
choices of the physician and the patient (Fig 1). Treatment was continued for at least the first
three months after AIS. The aLA dose was 600 mg once daily.

Statistical analysis
Differences between the groups were analyzed using Student’s t test, one-way ANOVA, or
Mann–Whitney test where appropriate. The chi-square test was used for non-continuous

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 Lipoic Acid Use and Functional Outcome of Stroke

Fig 1. The flow diagram shows the process of grouping of subjects from screening to the completion of the study.
doi:10.1371/journal.pone.0163484.g001

variables. Spearman’s and Pearson’s correlation tests were carried out to reveal any correla-
tions. The level of significance was set at a p value of <0.05.
The Cochran–Mantel–Haenszel (CMH) test carried out across the seven-level mRS score
for shift analysis and conventional dichotomized analysis were used to analyze the distributions
of the 3-months and 1-year mRS outcome scales [15]. We performed a backward stepwise
logistic regression analysis to assess the odds ratios (ORs) and the corresponding 95% confi-
dence intervals (CIs) for a favorable outcome according to the use of aLA. We used two

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 Lipoic Acid Use and Functional Outcome of Stroke

multivariable models. Model 1 was initially adjusted for age and gender. Potential factors
already established as predictors of stroke outcome were added to model 2.
Variables that were not significant (p >0.1) were sequentially removed from the full model.
The excluded potential confounders were reintroduced at various stages of model development
until only the significant independent variables remained. A two-sided p-value of <0.05 was
considered statistically significant. All statistical analyses were performed using PASW soft-
ware (version 18.0).

Results
Patient characteristics
The study included 172 patients with AIS and diabetes who were treated using thrombolysis.
Of the included patients, 47 (27.3%) were using aLA at the acute stage of stroke. Baseline clini-
cal and biochemical characteristics of the aLA users and the nonusers are shown in Table 1.
Vascular risk factors, biochemical variables, and stroke subtypes were not significantly different
between the two groups. There was also no difference in the initial NIHSS score or the onset to
intravenous thrombolysis (IVT) time.

Functional Outcomes
After 3 months, 67 patients (38.9%) had a favorable outcome (mRS score of 0–2). As shown in
Fig 2, the number of patients with a favorable outcome was significantly higher in the aLA user
group compared to the aLA non-user group (55.3 vs. 32.8%, p = 0.003; Fig 2A). Furthermore,
the percentage of patients who were living without a significant disability as measured by mRS
assessed 1 year after ischemic stroke (40.7% in total) was significantly higher in the group
treated with aLA (57.4% versus 34.4%, p = 0.004; Fig 2B). Next, we confirmed the above results
using the CMH test across the seven-level mRS scores for shift analysis. The CMH test revealed
a statistically significant shift in the 3-months and 1-year mRS distributions favoring aLA
(p < 0.001). Changes from baseline mRS up to 1 year after stroke showed favorable outcomes
by the treatment of aLA (Fig 3A).
Univariate analyses of variables associated with functional outcomes are shown in Table 2.
Age, atrial fibrillation, initial NIHSS score, and HT were significantly associated with func-
tional outcomes at 3 months and 1 year as determined by univariate analysis.
In the final multivariable analysis, which included adjustments for confounders, such as
age, sex, history of hypertension, atrial fibrillation, dyslipidemia, HT, and initial NIHSS score,
aLA use was significantly associated with a favorable outcome 3 months after ischemic stroke
(OR = 2.13, 95% CI [1.01, 4.51], p = 0.048; Table 3). Similarly, aLA use was still associated with
a favorable outcome 1 year after ischemic stroke (OR = 2.26, 95% CI [1.06, 4.84], p = 0.036;
Table 3). Age, HT, and increasing NIHSS scores were negative predictors of favorable out-
comes after adjusting for all potential factors (Table 3). The following values were selected
using multiple threshold estimations: age (70), and NIHSS score (8).

Early clinical outcomes

Forty-seven (27.3%) patients had ECI. END occurred in 34 (19.7%) cases. ECI was more preva-
lent in aLA users (40.4% vs. 22.4%, p = 0.030), whereas END was significantly less prevalent in
aLA users compared to patients not using aLA (10.6% vs. 23.2%, p = 0.036; Fig 3B). In the
entire cohort, HT was more often seen in patients not receiving aLA compared to patients
using aLA (31.2% vs. 14.9%, p = 0.017). However, the frequency of symptomatic HT was com-
parable between the two groups (4.8% vs. 2.1%, p = 0.432; Fig 3B).

PLOS ONE | DOI:10.1371/journal.pone.0163484 September 27, 2016 5 / 12

 Lipoic Acid Use and Functional Outcome of Stroke

Table 1. Baseline differences in clinical and biochemical characteristics according to the use of alpha-lipoic acid.
aLA (n = 47) No aLA (n = 125) p value*
Age, years 68.6 71.0 0.169
Male, n (%) 27 (57.4) 62 (49.6) 0.362
Risk factors, n (%)
Hypertension 34 (72.3) 99 (79.2) 0.341
Atrial fibrillation 17 (36.2) 43 (34.4) 0.829
Dyslipidemia 8 (17.0) 16 (12.8) 0.185
Coronary angioplasty 1 (2.1) 1 (0.8) 0.407
Smoking 15 (31.9) 35 (28.0) 0.617
Alcohol 15 (31.9) 40 (32.0) 0.398
Biochemical variables (mean ± SD)
Total-C, mg/dL 173.1± 41.4 176.7 ± 39.7 0.657
LDL-C, mg/dL 113.7± 35.7 113.5 ± 35.0 0.998
Triglyceride, mg/dL 102.4 ± 61.1 107.9 ± 53.0 0.604
HDL-C, mg/dL 44.3 ± 12.0 45.1 ± 16.4 0.789
Creatinine, mg/dL 0.8 ± 0.4 0.9 ± 0.3 0.680
Glycated hemoglobin, % 7.1 ± 1.9 7.3 ± 1.3 0.419
FBS, mg/dL 165.5 ± 72.4 179.0 ± 72.8 0.290
TOAST classification, n (%) 0.922
LAA 17 (36.2) 42 (33.6)
CE 14 (29.8) 41 (32.8)
SVO 3 (6.4) 6 (4.8)
UD 12 (25.5) 35 (28.0)
OE 1 (2.1) 1 (0.8)
Initial NIHSS score (mean ± SD) 9.5 ± 4.9 10.5 ± 4.9 0.149
Baseline mRS (mean ± SD) 3.3 ± 1.2 3.5 ± 1.3 0.443
Onset to IVT time (mean ± SD), min. 123.0 ± 67.8 132.1 ± 63.9 0.429
Discharge medication, n (%)
Statin 32 (68.1) 89 (71.8) 0.638
Antihypertensive drug 33 (70.2) 97 (77.6) 0.318

*Continuous variables were compared between groups using Student’s t tests, one-way ANOVAs, or Mann–Whitney tests. The chi-square test was used
for non-continuous variables.
Total-C = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; FBS = fasting blood sugar;
TOAST = Trial of Organization 10172 in Acute Stroke Treatment; LAA = large-artery atherosclerosis; CE = cardioembolism; SVO = small-vessel occlusion;
UD = stroke of undetermined etiology; OD = stroke of other determined etiology; NIHSS = National Institutes of Health Stroke Scale; SD = standard
deviation; mRS = modified Rankin Scale; IVT = intravenous thrombolysis

doi:10.1371/journal.pone.0163484.t001

Discussion
This is the first study to evaluate the effects of aLA in a cohort of patients with diabetes and
acute stroke treated with a thrombolytic agent. This study showed that patients with diabetes
treated with aLA have better functional outcomes following AIS after reperfusion therapy than
patients not using aLA. Previously, we demonstrated the neuroprotective and neurorestorative
effects of aLA after cerebral ischemia in rats subjected to middle cerebral artery occlusion [5].
The results of the current study indicate that aLA use after IVT is independently associated
with favorable outcomes (mRS scores of 0–2) 3 months and 1 year after ischemic stroke. Our
study suggests that patients treated with aLA may have better long-term functional outcomes

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 Lipoic Acid Use and Functional Outcome of Stroke

Fig 2. Distribution of the modified Rankin Scale (mRS) scores among patients classified based on the use of alpha-
lipoic acid (aLA) 3 months (A) and 1 year (B) after ischemic stroke. The lines indicate differences in mRS categories (mRS
scores of 0–2 vs. 3–6) between groups classified by aLA use. The p-value refers to the significance level of the chi-square test
used to compare proportions.
doi:10.1371/journal.pone.0163484.g002

than patients not using aLA. The findings highlight the importance of antioxidants in patients
treated with thrombolysis to improve the outcome of AIS. Given the numerous failures in the
clinical translation of neuroprotective treatment for patients with AIS, the current results are of
potential importance in the clinical setting.

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 Lipoic Acid Use and Functional Outcome of Stroke

Fig 3. (A) Changes from baseline modified Rankin Scale (mRS) up to 1 year after stroke. (B) Proportion of patients with
early clinical outcomes and hemorrhagic transformation displayed according to the use of alpha-lipoic acid (aLA). *p < 0.01
vs. no-aLA group; the chi-square test was used to compare proportions. ECI = early clinical improvement; END = early
neurological deterioration; HT = hemorrhagic transformation; sHT = symptomatic hemorrhagic transformation.
doi:10.1371/journal.pone.0163484.g003

The mechanisms by which aLA provides benefits to patients with AIS may be related to the
antioxidant properties of aLA. Oxidative stress is one of the leading causes of brain damage in
ischemia-reperfusion injury [2], and aLA is a strong antioxidant that influences a number of
cellular processes, including the scavenging of reactive oxygen species (ROS), the regeneration

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 Lipoic Acid Use and Functional Outcome of Stroke

Table 2. Variables related to functional outcomes at 3 months and 1 year used in univariate analyses.
3-month outcomes 1-year outcomes
Patients with mRS Patients with mRS p Patients with mRS Patients with mRS p
scores of 0–2 (n = 67) scores >2 (n = 105) value* scores of 0–2 (n = 70) scores >2 (n = 102) value*
Age, years 66.5 72.7 <0.001 65.7 73.5 <0.001
Male, n (%) 41 (61.2) 48 (45.7) 0.060 42 (60.0) 47 (46.1) 0.088
aLA use, n (%) 26 (38.8) 21 (20.0) 0.009 27 (38.6) 20 (19.6) 0.009
Risk factors, n (%)
Hypertension 52 (77.6) 81 (77.1) 1.000 55 (78.6) 78 (76.5) 0.853
Atrial fibrillation 17 (25.4) 43 (41.0) 0.049 18 (25.7) 42 (41.2) 0.049
Dyslipidemia 9 (13.4) 15 (14.3) 0.809 9 (12.8) 15 (14.7) 0.564
Coronary angioplasty 1 (1.5) 1 (0.9) 0.407 1 (1.5) 1 (0.9) 0.407
Smoking 21 (31.3) 29 (27.6) 0.610 22 (31.4) 28 (27.5) 0.610
Alcohol 20 (29.8) 35 (33.3) 0.398 21 (30.0) 34 (33.3) 0.319
Biochemical variables (mean ± SD)
Total-C, mg/dL 178.4 ± 43.7 173.9 ± 45.9 0.527 177.4 ± 39.1 174.5 ± 48.8 0.679
LDL-C, mg/dL 116.5 ± 43.6 111.6 ± 43.2 0.493 114.1 ± 39.4 113.3 ± 46.0 0.908
Triglyceride, mg/dL 102.5 ± 54.5 109.1 ± 65.1 0.496 101.8 ± 53.5 109.8 ± 65.9 0.406
HDL-C, mg/dL 45.6 ± 12.8 44.3 ± 14.2 0.573 46.7 ± 13.3 43.5 ± 13.7 0.141
Creatinine, mg/dL 0.8 ± 0.3 0.9 ± 0.6 0.155 0.8 ± 0.4 0.9 ± 0.6 0.123
Glycated hemoglobin, % 7.3 ± 1.5 7.2 ± 1.5 0.682 7.3 ± 1.5 7.2 ± 1.5 0.781
FBS, mg/dL 172.7 ± 72.1 177.2 ± 72.9 0.702 170.2 ± 71.7 178.9 ± 73.0 0.448
Initial NIHSS (mean ± SD) 8.1 ± 3.5 11.7 ± 4.5 <0.001 8.1 ± 3.6 11.8 ± 4.4 <0.001
Onset to IVT (mean ± SD), min. 124.8 ± 63.2 132.5 ± 66.2 0.468 122.2 ± 65.1 134.6 ± 64.7 0.237
TOAST classification, n (%)† 17 (25.4) 38 (36.2) 0.180 18 (25.7) 37 (36.3) 0.183
Hemorrhagic transformation, n (%) 8 (11.9) 38 (36.2) <0.001 10 (14.3) 36 (35.3) 0.003

*Continuous variables were compared between the groups using Student’s t tests, one-way ANOVAs, or Mann–Whitney tests. The chi-square test was
used for non-continuous variables.
†
Percentage relates to cardiac embolism, because this cause was associated with a worse outcome.
Total-C = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; FBS = fasting blood sugar;
NIHSS = National Institutes of Health Stroke Scale; IVT = intravenous thrombolysis; TOAST = Trial of Organization 10172 in Acute Stroke Treatment;
aLA = alpha-lipoic acid; SD = standard deviation

doi:10.1371/journal.pone.0163484.t002

Table 3. Final logistic regression model with predictors of favorable outcome*.

Independent Variables Outcomes (hazard ratio [95% CI])
3-month outcomes 1-year outcomes
Model 1 Model 2 Model 1 Model 2
aLA use 2.687 [1.014, 4.819] 2.134 [1.008, 4.517] 2.817 [1.074, 4.897] 2.258 [1.055, 4.835]
Age (70) 0.468 [0.243, 0.902] 0.493 [0.253, 0.958] 0.306 [0.157, 0.596] 0.317 [0.161, 0.622]
Male 0.543 [0.219, 1.131] 0.588 [0.261, 1.194] 0.631 [0.287, 1.912] 0.710 [0.329, 1.530]
Hypertension 1.052 [0.485, 2.283] 1.139 [0.505, 2.568] 1.162 [0.526, 2.570] 1.256 [0.551, 2.864]
Atrial fibrillation 0.607 [0.300, 1.227] 0.674 [0.315, 1.445] 0.637 [0.313, 1.298] 0.671 [0.313, 1.442]
Dyslipidemia 0.934 [0.339, 2.573] 1.318 [0.440, 3.955] 1.148 [0.415, 3.175] 1.550 [0.522, 4.602]
Hemorrhagic transformation 0.243 [0.100, 0.589] 0.283 [0.113, 0.710] 0.343 [0.146, 0.802] 0.403 [0.165, 0.982]
Initial NIHSS score (8) 0.256 [0.127, 0.516] 0.266 [0.129, 0.546] 0.264 [0.129, 0.541] 0.269 [0.129, 0.565]

* Model 1 was adjusted for age and gender. Model 2 was adjusted for the variables in model 1 plus factors already established as predictors of stroke
outcome and differed significantly between the outcome groups in univariate analysis. CI = confidence interval; NIHSS = National Institutes of Health Stroke
Scale

doi:10.1371/journal.pone.0163484.t003

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 Lipoic Acid Use and Functional Outcome of Stroke

of reduced forms of other antioxidants, and the modulation of transcription factor activity. It
has been shown that aLA is able to repair oxidative damage, regenerate endogenous antioxi-
dants, improve endothelial function and blood flow, and accelerate glutathione synthesis,
which plays a crucial role in preventing damage caused by ROS to important cellular compo-
nents [16–19].
In addition, the possible mechanism by which aLA promotes favorable outcomes may be
related to activation of the insulin receptor (IR). In our previous study, the effects of aLA were
significantly associated with IR activation, which is a well-known neuroprotective pathway in
ischemic models [5, 20–22]. aLA has been reported to be safe and effective in the treatment of
aged patients with diabetes mellitus complicated by AIS. It has been shown to significantly
reduce the patient's oxidative stress and blood glucose and lipid levels, and to improve islet
function in a previous study [6]. Because only diabetic patients were enrolled in our study, aLA
may appear to be more useful in improving ischemic stroke than in other studies that include
non-diabetic patients.
A previous study has shown that aLA has a stabilizing effect on the blood-brain barrier
(BBB), making aLA an attractive therapeutic agent for the treatment of stroke [23]. BBB dam-
age is a common event in ischemic stroke and is aggravated by reperfusion [24, 25]. Therefore,
one of the most important targets for the effective treatment of cerebral ischemia is the protec-
tion of the BBB against damage [26]. HT, one of the most serious complications of ischemic
stroke, is induced by the disruption of the BBB after ischemia-reperfusion [25]. In our study,
HT was a significant independent negative predictor of favorable outcome after AIS in patients
treated using thrombolysis. Importantly, HT was less prevalent in aLA users compared to
patients not using aLA. This may be a major mechanism underlying the positive effects of aLA.
In addition to HT, age and increased NIHSS scores have already been established as negative
predictors of favorable outcomes. These factors remained negative predictors of favorable out-
comes after adjusting for all potential factors. These findings are similar to those of previous
reports of outcome measures in patients treated with thrombolytics [27, 28].
This study has limitations. First, it was based on a nonrandomized prospective registry with
a relatively small number of patients. Therefore, there is a risk of bias from unmeasured or
residual confounders despite adjustments for covariates. Although this was a retrospective
study, we prospectively collected data in consecutive patients. Second, recanalization was not
analyzed in this study and could affect the prognosis. Because we performed non-contrast CT-
based IV thrombolysis, we could not confirm recanalization in the patients. Finally, data from
the literature indicate that the effects of aLA depend on the dose used [29]. However, we cannot
be sure of the doses and the durations of the aLA pretreatment. It is thus possible that the bene-
ficial effects depend on the duration of treatment before stroke. However, there was no with-
drawal of aLA in the acute phase of stroke or after hospitalization.
In conclusion, we show, for the first time, a beneficial effect of aLA on ischemia-reperfusion
injury in patients with diabetes and AIS. These results indicate that aLA could be a useful inter-
vention for the treatment of AIS after reperfusion therapy. Despite the acknowledged limita-
tions of our study, this analysis may have implications for future multicenter randomized
trials. One such trial is currently being performed and will be the subject of a following study
(IMpact of liPOic acid use on stRoke ouTcome After thrombolysis in patieNts with diabeTes
[IMPORTANT]; Honam Research Council of Stroke of Korea).

Author Contributions
Conceptualization: K.H. Choi MSP.
Data curation: K.H. Choi MSP JHK.

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 Lipoic Acid Use and Functional Outcome of Stroke

Formal analysis: K.H. Choi MSP JHK.

Funding acquisition: K.H. Choi.
Methodology: K.H. Choi MSP JTK.
Resources: HSK JHK.
Writing – original draft: K.H. Choi.
Writing – review & editing: K.H. Choi MSP JTK HSK TSN SMC SHL BCK MKK K.H. Cho.

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